Pharmacological evidence indicates that D2 dopaminergic (D2R) and A2a adenosinergic (A2aR) receptors interact to modulate motor function. Until recently little was known about the anatomical and cellular basis of this interaction between A2aR and D2R. We recently demonstrated that A2aR mRNA and D2R are exclusively co-expressed in a subset of rat striatal neurons which comprise the striatopallidal or "indirect" pathway of striatal efferent neurons to the major basal ganglia output nuclei. The A2aR, therefore, is located in a potentially powerful position for modulating activity in the striatopallidal pathway. No other neurotransmitter receptor has been identified which is expressed in as influential a position to selectively regulate the response of the motor system to D2R activation. The overall hypothesis of Project 3 is that interaction between A2aRs and D2Rs occurs in an subset striatal neurons and effects changes in motor behavior by regulating activity in the "indirect" striatopallidal pathway in rodents and humans. Anatomical and pharmacological evidence strongly suggests that the A2AR is of considerable importance to understanding the pathophysiology of movement disorders and the design of effective treatments. However, the cellular mechanisms by which A2aR and D2R interact to modulate motor function are not understood. Therefore, in Project 3 we propose to investigate several aspects of the biology of the A2aR particularly with reference to the human A2aR. In this Project we will characterize the (1) structure of the human A2aR gene, (2) the anatomical expression of the human A2aR gene and its protein product within the human striatum, (3) changes in activity of striatopallidal neurons in vivo resulting from interaction between A2aR and D2R, (4) the cellular mechanisms by which A2aR and D2Rs may interact to regulate activity within cells of the indirect striatal efferent pathway and (5) the mechanisms by which expression of the rat A2aR gene is regulated. These studies will provide important information about the receptor and cellular mechanisms by which A2aR and D2Rs interact to regulate motor function in human movement disorders and, possible, reveal novel approaches for regulating motor function through the "indirect" striatal efferent pathway.